Antimicrobial peptides are effector molecules of the innate immune system and contribute to host defense and regulation of inflammation. The human cathelicidin antimicrobial peptide LL-37/hCAP-18 is expressed in leukocytes and epithelial cells and secreted into wound and airway surface fluid. Here we show that LL-37 induces angiogenesis mediated by formyl peptide receptor–like 1 expressed on endothelial cells. Application of LL-37 resulted in neovascularization in the chorioallantoic membrane assay and in a rabbit model of hind-limb ischemia. The peptide directly activates endothelial cells, resulting in increased proliferation and formation of vessel-like structures in cultivated endothelial cells. Decreased vascularization during wound repair in mice deficient for CRAMP, the murine homologue of LL-37/hCAP-18, shows that cathelicidin-mediated angiogenesis is important for cutaneous wound neovascularization in vivo. Taken together, these findings demonstrate that LL-37/hCAP-18 is a multifunctional antimicrobial peptide with a central role in innate immunity by linking host defense and inflammation with angiogenesis and arteriogenesis
Previous studies have implicated antimicrobial peptides in the host defense of the mammalian intestinal and respiratory tract. The aim of the present study has been to characterize further the expression of these molecules in non-epithelial cells of the human pulmonary and digestive systems by detailed immunohistochemical analysis of the small and large bowel and of the large airways and lung parenchyma. Additionally, cells obtained from bronchoalveolar lavage were analyzed by fluorescent activated cell sorting and immunostaining of cytospin preparations. hBD-1, hBD-2, and LL-37 were detected in lymphocytes and macrophages in the large airways, lung parenchyma, duodenum, and colon. Lymphocytes positive for the peptides revealed a staining pattern and distribution that largely matched that of CD3-positive and CD8-positive T-cells. Macrophages with positive staining for the antimicrobial peptides also stained positively for CD68 and CD74. In view of the morphology of the LL-37-positive and hBD-2-positive mucosal lymphocytes, they are probably also B-cells. Thus, antimicrobial peptides of the defensin and cathelicidin families are present in a variety of non-epithelial cells of mucosal organs. These findings confirm that antimicrobial peptides have multiple functions in the biology of the mucosa of these organs.
Cell proliferation, apoptosis, and the expression of Bcl-2 and Bax were investigated in breast tissue of healthy premenopausal women in order to study the effect of the menstrual cycle and reproductive history on the cell turnover in the non-lactating mammary gland epithelium. Immunohistochemistry was used to detect the proliferation-associated antigen Ki-67, as well as Bcl-2 and Bax. Apoptotic cells were identified by enzymatic labelling of fragmentized DNA (TUNEL-technique) and morphologic analysis. Consistent with published data, the proliferative activity and the frequency of apoptotic events as detected by morphologic analysis was higher in the luteal than in the follicular phase of the menstrual cycle. Parity, lactation, and age correlated with lower proliferative activity, whereas the frequency of apoptosis was not significantly influenced by the reproductive history. Staining patterns for Bax and Bcl-2 showed characteristic changes due to the menstrual cycle with a maximum of immunoreactivity for Bcl-2 in the follicular phase and for Bax in the luteal phase. However, there was no statistically significant association between Bcl-2/Bax immunoreactivity and menstrual cycle or reproductive parameters. We conclude that other molecular pathways than the Bax/Bcl-2 antagonism may additionally be involved in the regulation of apoptotic cell death in the breast epithelium. Knowledge of the entire complexity of apoptosis regulation is necessary to understand the observed effects of parity and lactation on mammary epithelial biology, and possibly to be able to influence pathological processes caused by an imbalance between cell renewal and elimination.
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